Abstract

902

The majority of the human genome encodes for a large number of noncoding RNA (ncRNA) species excluding ribosomal RNAs and transfer RNAs. Emerging studies suggest that ncRNAs have important biological functions in different biological processes. Although ncRNAs could also play a role in human diseases, experimental evidence has been scarce. Here, we provide evidence for the role of an intron-derived small nucleolar RNA (snoRNA), one common class of ncRNAs, in the development of human cancer. The U50 snoRNA was located at 6q15, a locus frequently deleted in human cancer. A homozygous 2-bp deletion in the U50 gene was detected both somatically and in germline in 11 of 119 (9%) prostate cancer samples, but not in any of 104 normal controls, whereas a heterozygous genotype occurred at similar rates between cancers and controls. More definitively, analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, whereas a heterozygous genotype of the deletion was relatively frequent in germ DNA from both cases and controls and was not associated with prostate cancer, its homozygous genotype significantly predicted prostate cancer. In addition, this mutation abolished the function of U50 in an in vitro cell growth assay. These findings indicate that mutations of ncRNAs occur and play a role in human diseases. They also establish a new class of cancer genes and present snoRNA U50 as a reasonable candidate for the 6q15 tumor suppressor gene in human cancers.